Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer’s disease

Background

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and affects one out of ten individuals above the age of 65 in the US. Although older age is the major risk factor for developing AD, the exact role of brain aging in disease pathogenesis remains elusive. The characteristic features of AD pathology are amyloid plaques, neurofibrillary tangles and loss of neuronal connections in the brain (1). The plaques mainly consist of beta-amyloid (Aβ) peptides, which are generated through cleavage of the amyloid precursor protein (APP) by secretases, such as beta-site APP-cleavage enzyme 1 (BACE1). Typically, these plaques are surrounded by microglia, specialized immune cells which among others “clean up” the brain by phagocytosing cell debris and unwanted materials such as Aβ plaques. There is evidence that microglia form a protective barrier around amyloid aggregates to prevent further Aβ accumulation (2). However, with increasing age, microglia face greater challenges due to increased production of cellular waste. For example, the degradation of myelin, which forms a compact lipid-rich sheath around neuronal axons to facilitate conduction speed, is markedly increased in the aging human brain (3). Consequently, the authors of this preprint hypothesized that defective myelin prevents microglia from clearing Aβ, thus contributing to the development of AD. Moreover, they speculated that loss of myelin integrity triggers the formation of Aβ plaques. To investigate the impact of impaired myelin on AD pathogenesis, they used various mouse models with genetically or chemically induced myelin dysfunction.

Key findings

In the first part of the study, Depp et al. assessed amyloid deposition in AD mouse models (5xFAD and APP^NLGF, respectively) crossed with mice showing minor structural myelin defects driven by the lack of myelin-proteins like CNP (CNP^-/-) or PLP (PLP^-/y). 5XFAD mice harbor five familial AD (FAD) mutations triggering Aβ overproduction, and already exhibit amyloid deposition two months after birth (4). Light-sheet microscopy analysis revealed that 6-month-old CNP^-/- 5xFAD and PLP1^-/y 5xFAD double mutants exhibited a higher load of amyloid plaques than 5xFAD mice. A similar phenotype was described for 6-month-old CNP^-/-APP^NLGF double mutant mice.

To further investigate whether myelin defects can cause plaque deposition, they induced acute demyelination in 5xFAD mice by feeding them Cuprizone. Although this copper chelator could possibly interfere with plaque formation, Cuprizone-treated mice showed a substantial increase of amyloid aggregates in regions of strong demyelination. Similarly, induction of experimental autoimmune encephalomyelitis (EAE) – a model for chronic immune-mediated myelin loss – caused the formation of amyloid plaques in the spinal cord of 5xFAD mice. This indicates that chronic and acute myelin dysfunction trigger amyloid deposition and reveals myelin defects as a risk factor for plaque formation.

Compared to smaller animals, the amount of myelin in the human brain is much higher, thus the extend of cortical myelination itself might play a role in AD pathogenesis. In the following, Depp et al. investigated the impact of severe reduction of cortical myelin on amyloid pathology. Therefore, they created a mouse model with sparsely myelinated cortical axons (forebrain shiverer mice, Emx-Cre MBP^fl/fl) and combined them with 5xFAD mice. In these mice, plaque formation was notably reduced at three months of age, but this protective effect was no longer observed in 6-month-old animals. This indicates that absence of myelin delays amyloid deposition.

Next, the authors analyzed how APP metabolism is affected by myelin dysfunction. In 6-month-old CNP-/-5xFAD mice, they observed increased expression of BACE1 accompanied by elevated levels of APP fragments, which suggests enhanced Aβ generation driven by defective myelin.

Finally, Depp and colleagues examined the reaction of microglia to Aβ deposition in an environment with myelin defects. Although glial cells were strongly activated in CNP^-/-5xFAD and CNP^-/- APP^NGLF mice, microglia did not display the typical plaque-surrounding behavior. RNA sequencing analysis confirmed that in these mice the “myelin dysfunction” signature dominated the transcriptome of microglia. Overall, based on their findings, the authors suggest that myelin-clearing microglia are distracted from plaques, thus enhancing amyloid deposition. Additionally, this process could be further accelerated by the secretion of pathogenic factors.

Why I chose this preprint

AD is one of best characterized neurodegenerative diseases, however, why aging is the major risk factor is still a mystery. In this preprint, Depp et al. propose an intriguing mechanism explaining the link between brain aging and amyloid pathology. To test their hypothesis, they take sophisticated approaches by generating various mouse lines and using complex methods including light sheet microscopy and an extensive transcriptomic analysis.

I did my PhD in neuroimmunology and mainly worked with demyelinating models such as Cuprizone and EAE. Among others, I investigated the role of alpha-synuclein – an aggregation-prone protein associated with Parkinson’s disease – in neuroinflammation. Thus, I find it particularly interesting to learn about the potential link of pathologic protein deposition and myelin defects.

Questions to the authors

1. Do you think that distraction of microglia by myelin breakdown could also play a role in other neurodegenerative diseases with protein aggregations such as Parkinson’s disease?
2. Would it be possible to change the focus of microglia once they are distracted by myelin debris and urge them to react to amyloid aggregates?

References

1. 2020 Alzheimer’s disease facts and figures. Alzheimer’s Dement 2020; 16: 391-460. https://doi.org/10.1002/alz.12068
2. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018 Feb 5;217(2):459-472. doi: 10.1083/jcb.201709069.
3. Papuć E, Rejdak K. The role of myelin damage in Alzheimer’s disease pathology. Arch Med Sci. 2018 Aug 28;16(2):345-351. doi: 10.5114/aoms.2018.76863. PMID: 32190145; PMCID: PMC7069444.
4. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006 Oct 4;26(40):10129-40. doi: 10.1523/JNEUROSCI.1202-06.2006.

Tags: alzheimer's disease, microglia, myelin dysfunction

doi: https://doi.org/10.1242/prelights.30374

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